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Vol. LVII, No. 10
May 20, 2005

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Developing 'Happily Ever Afters'
Pediatric Cancer Progress Slow, But Steady

On the front page...

For the legion of youngsters clamoring to have designer jeans and other high-priced trendy items, there is also a smaller, no less vocal group pushing on behalf of kids for other expensive, but much more crucial, tailor-made products — designer drugs. It's the growing trend toward individualized medicine — no more evident than in research on childhood cancers — that presents both promise and problems in efforts against the disease, according to scientists at an Apr. 26 NCI/Children's Inn seminar.

"How do we get further?" asked Dr. Alan Wayne, clinical director of the Pediatric Oncology Branch at NCI's Center for Cancer Research. "As with any big complex problem in our complex society, we do it in a multifaceted, collaborative way. More and more it takes collaboration from government, private industry, philanthropic organizations and regulatory bodies like the FDA, as well as altruism, voices in the media and grassroots efforts — basically it takes everybody working together with common goals."


Where We've Been

Dr. Alan Wayne of NCI  
Many can remember the days when a diagnosis of childhood acute lymphoblastic leukemia (ALL) was "a death sentence and survivals were poor," Wayne recalled. "In the 1960s to 70s, less than 5 percent survived long term. Because of systematic improvements in therapy — and particularly pediatric cooperative group trials here in North America — there have been steady improvements such that now when children are diagnosed with ALL they have an 80 — potentially 90 — percent chance of cure."

Nonetheless, cancer is the number one cause of death from disease in pediatrics, he said.

Approximately 1,600 cancer-related deaths occur each year in children under age 21. Of the deaths from cancer, one third are the result of leukemia, mainly ALL, which is the most common pediatric cancer diagnosis.

"Up until a few decades ago, leukemia was defined as a fatal disorder of the blood-forming organs," stressed Dr. Donald Small of Johns Hopkins University School of Medicine. "That is something that has very much changed over time, thanks to improvements in therapy."

Small, the Kyle Haydock professor of oncology at JHU's Sidney Kimmel Comprehensive Cancer Center, described several factors that have boosted cure rates:

  • Pediatric clinical trials — "Most of the drugs used to fight childhood cancers have been around a long time," but the progression of clinical studies in kids allowed doctors to discover how best to combine the drugs.
  • Combinations of chemotherapy — Doctors have learned to use different drugs together to attack tumors.
  • Treating spinal fluid, "which serves as a sanctuary where cancer cells grow."

In addition, he explained, doctors can now better estimate patient risk factors in order to change therapy, depending on how high the child's relapse risk is. That was not possible even a decade ago.

Wayne said bone marrow transplantation also has contributed to better cancer-free survival. "Donor lymphocytes can eradicate cancer cells without chemotherapy in an immunologic reaction referred to as the 'allogeneic graft-versus-tumor effect,'" he explained.

Where We're Going

Researchers are now studying the biology of immune effectors and targets of the immune reaction in order to develop therapies using immune system cells as primary cancer treatments. Wayne said his team is working on the first pediatric cancer clinical trial of an allogeneic tumor vaccine.

Dr. Donald Small of Johns Hopkins describes several factors that have boosted cure rates. NCI Pediatric Oncology Branch chief Dr. Lee Helman addresses moral and ethical concerns raised by a burgeoning
era of designer therapy.

Another new approach uses information derived from genomic studies, he continued. "What is clear not just in leukemia but in all cancers is that the story lies in the biology of the disease," he explained. "Chromosome and gene abnormalities inside leukemia cells influence the outlook for a given individual. Genetic analysis now allows us to identify children at greater risk of relapse who need more intensive therapy. In addition, this technology can be used to point out potential targets for therapeutics."

To illustrate the promise of targeted drugs and the importance of pediatric clinical trials, Wayne told the story of Killian Owen, a 9 -year-old boy with ALL who became the first child to receive BL22. [see sidebar below]

"Kids and families who work with us on these early developmental trials absolutely know that the decks are stacked against them," Wayne said. "However, they come to NIH with hope and a huge dose of altruism. Yes, they are looking for magic bullets and we are trying to design magic bullets. Ultimately when we come together here, most everybody realizes that a miracle would be great for the individual child, but the likely outcome will be a step forward in the very steady, systematic progress in the war on pediatric cancer."

Steady progress, he pointed out, is based on rigorous scientific work, which requires huge effort and resources. It also takes years of intense teamwork. As examples, Wayne discussed several drugs that target leukemia and are in the clinical trial pipeline for kids:

  • BL22, which Killian Owen was the first child to receive, was developed at NCI and now with pharmaceutical partner Genencor. Doctors have given the agent to more than a dozen children in a phase I study at NCI.
  • LMB2, a similar agent also designed by NCI to target a different protein than BL22 found on the surface of certain cancer cells, is also now under study in children.
  • HA22, a newer generation agent related to BL22, is under development jointly by NCI and Genencor.

Small predicted that similar tailored therapies are the near future of cancer treatment. "Ultimately what will happen," he said, "is people will come in with a tumor. We'll determine each individual's

Pioneers in Pediatric Cancer Drug Therapy
Owen Family Made Memories, History

Ten days before Christmas and just a couple of weeks before the predicted Y2K D-day, a Georgia family of six experienced a devastating event of its own: 5-year-old Killian Owen was diagnosed with leukemia. In the 30 months ahead, Killian would wage a fierce battle with the disease that accounts for about 30 to 40 percent of childhood cancers.

One legacy of Killian Owen is the fundraiser his parents started to help other kids with cancer.  

By early 2003, after exhaustive treatments with several rounds of chemotherapy and a bone marrow transplant procedure (using marrow donated by fraternal twin brother Garrett), Killian suffered yet another relapse.

"At that time we were told pretty much 'we could do nothing [more],'" recalled dad Clay recently at the Children's Inn at NIH. "We were told to go make some memories, so we did."

The Owens whisked their four sons off to Disney World to shore up the good times. However, when they returned home, mom Grainne refused to sit and wait for what they thought was inevitable. She went to work searching the Internet for answers. There had to be something, some experimental drug or some final treatment option available to Killian. Sure enough, she found a glimmer of hope in an online article about a doctor at Emory University investigating what he described as a targeted therapy.

Killian’s parents, Clay and Grainne Owen, discuss the tribute they began in his memory.

"Traditional chemotherapy had failed," she explained. "Bone marrow transplantation had failed. But, a drug called BL22 was designed for children with chemo-resistant leukemia, which Killian had."

Within a week or so, her research led her and the entire family to NIH and the inn.

"At that point, we really were hoping for the Hollywood ending," Clay said.

Killian became the first child to receive BL22, a new drug targeted to kill cells specific to his cancer.

"We were made very aware of all the risks," Grainne stressed, choking with emotion. "But you see at that point he was dying anyway. What did it matter if there were risks, because there was no hope otherwise. The fact that Killian was given a chance has led to so much hope for so many other children."

For several reasons, drug companies often hesitate to offer new drugs for pediatric clinical trials, pointed out Dr. Lee Helman, chief of the Pediatric Oncology Branch at NCI's Center for Cancer Research.

"A lot of the drug companies are reluctant to move any of these drugs into pediatric clinical trials," he said. "Pediatrics is not a really big market and companies are worried that adverse events that may occur in pediatric trials will ruin chances for approval of the drug in adults."

That's why Killian's participation in the BL22 trial was an important milestone in the fight against pediatric cancer.

"The Owen family played a pivotal role in releasing a logjam," explained Dr. Alan Wayne, clinical director of Helman's branch. "Those logjams are opening daily. The old paradigm — where drugs have to go from mice to monkeys to adults to children — is changing. The lessons [learned from treating Killian] are clearly important. Those of us involved in the scientific work feel more and more optimistic every day, based on translating advances at the bench to movement forward in the clinic."

The Hollywood ending did not happen for the Owen family, though. BL22 was not able to save Killian, who died at age 9 in July 2003. However, hope for other children is what brought mom and dad Owen back to the inn.

"There is a desperate lack of money in funding childhood cancer research," Grainne explained. "You shouldn't have to jump through the hoops that we had to jump through to get your child to try a new drug. Two classrooms full of children are being diagnosed [with cancer] every single day; one in four of those children is going to die. That is an amazing thought, that we're allowing that to happen. And a lot of it is due to lack of funding."

The Owen family launched Coaches Curing Kids' Cancer, a nationwide fundraiser that benefits CureSearch and the National Childhood Cancer Foundation. Instead of buying little league coaches a trinket or trophy at the end of a season, team families pool their donations and send the amount to the fundraiser to help further cancer research and its related expenses.

"We're going to get families in America behind this initiative," Grainne declared. "We're going to raise awareness of childhood cancer. We believe that it is possible to find cures to childhood cancers in our lifetime. The technology, the science is there. Killian's dream was to be a normal healthy child — a very simple dream. Combine the power of science with the power of the normal happy emotions that go with having normal healthy children and help us find a cure for childhood cancer."

For more information on Killian's legacy and the charitable foundation, visit

mutations. [Then] we'll pull off the shelf a specific inhibitor for a designer therapy."

However, such progress cannot occur without the help of brave pioneers like the Owen family, who become partners with the research community, said Wayne.

"Though the ultimate cure wasn't achieved for Killian," he remarked, "I don't consider his case a failure. From a purely scientific standpoint, we continue to use Killian's cancer cells and data to help us develop a treatment that we hope will someday have a place in the curative outcome for children like him in the future.

"Killian really does live on and continues to help us in many ways," he concluded. "Families like the Owens highlight the highs and lows of pediatric cancer therapy. Their experiences show us where we've come from and where we need to go, which is critical. We hope to get to the point where folks like the Owens only have happily-ever-afters."

Detours Along the Way

Small also discussed another common childhood cancer, acute myeloblastic leukemia (AML). The AML cure rate is only 40 percent. AML cells are much more resistant to chemotherapy. He said researchers have spent the last few decades defining changes that turn normally growing cells into abnormally growing cells, or cancer. His group cloned the human gene FLT3, which was later discovered by a team in Japan to have a mutation that is instrumental in turning good cells bad in some patients.

"[Expression of the FLT3 gene] takes a disease that is really, really bad and makes it worse," Small explained. "These patients have very little chance of cure."

Because of the FLT3 data, he continued, a number of research teams have launched aggressive searches for FLT3 inhibitors. Several agents already have been identified, including a drug called CEP-701 that Small's team is now ushering through various clinical trial design and approval stages.

"Unfortunately chemotherapy is the best we have to deal with these tumors, and we have gotten some really good cure rates with chemo for certain types of tumors," Small said. "But really all they are is poisons that kill rapidly proliferating cells, but also kill normal cells that proliferate as well. In addition, because these chemotherapies are non-specific, they can damage non-proliferating cells as well, so you can get side effects that damage the brain, heart and liver — just about any organ. [Scientists are now focusing on] molecular targeted therapy, where you have small molecules that kill only the cells that have the targeted protein in them and will leave normal proliferating cells unaffected and should have no effect on non-proliferating cells."

NCI Pediatric Oncology Branch chief Dr. Lee Helman, who studies solid tumors in children, offered a sobering summary of the battle against cancer that has spread.

"While progress has been good for non-metastatic disease," he said, "little progress has been made for patients diagnosed with widely spread cancer.For children who walk in our doors with disseminated disease, we really haven't changed things in 25 years. We're very unhappy about that and we're not going to stand for it."

His group is researching how to identify tumors that demonstrate aggressive behavior. Already they have found a protein that regulates metastasis. Soon, they will publish results of their successful attempts to use proteomics — the study of proteins in a cell or tissue — to predict cancer recurrence probability.

"We don't view pediatric deaths as statistics," he said. "Every single child who dies of pediatric cancer is a real catastrophe, a real tragedy."

Helman also talked frankly about the economics of cancer research and treatment. For example, he said that in the United States, about 10,000 cases of adult leukemia occur each year, with about 40 percent (4,000 cases) expressing the FLT3 gene. In contrast, there are 3,000 pediatric leukemia cases per year, with 15 percent (450) of those diagnosed with AML. A quarter of those express the FLT3 mutation, he said, "so you're looking at just about 100 cases — not much of a monetary incentive" for companies to develop the drug.

Finally, Helman addressed moral and ethical concerns raised by a burgeoning era of designer therapy. It's fortunate, he said, that so far, so many aspects of cancer biology have been universal, their lessons transferable from patient to patient, whether adults or children. "But," he concluded, "there will be unique features that are totally specific to a cancer and that's where the industry — and we as a society — deal with individualized therapy. What if we find a drug that totally cures just 300 cancers? Who's going to pay for developing that drug? There are huge ramifications."

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